Oxytocin was one of the first peptide hormones to be isolated and sequenced. It is a nonapeptide with two cysteine residues that form a disulfide bridge between positions 1 and 6 and corresponds to the formula

For a long time the only effects attributed to oxytocin were its stimulating effects on milk ejection and uterine contractions, but in the past decades it has been shown that oxytocin exerts a wide spectrum of effects within the central nervous system, CNS. It has been suggested that oxytocin participates in the control of memory and learning processes and of various types of behaviour such as feeding, locomotion, as well as maternal and sexual behaviour. Oxytocin is also suggested to participate in the control of cardiovascular functions, thermoregulation, pain threshold and fluid balance, as well as in wound healing. There is also evidence that oxytocin is involved in the control of various immunological processes. It has also been demonstrated that oxytocin injections cause a lowering of blood pressure and increased weight gain with long lasting effects after repetitive administration. As a central stimulating substance oxytocin plays an important role in the interaction between mother and progeny in mammals. The products may also be used as prophylactics in young human beings e.g. already in new born babies or young children to prevent the development of diseases later on in life, which diseases are dependent on stress conditions during the fetal life. Such conditions may be heart/vessel diseases such as stroke, heart infarct, hypertension, and diabetes. In the human body oxytocin is produced in the paraventricular nucleus, PVN, and the supraoptic nucleus, SON, of the hypothalamus. It differs by only two amino acids from vasopressin, which is also produced in these nuclei. The magnocellular oxytocinergic neurones of the SON and PVN send oxons to the posterior pituitary from which oxytocin is released into the circulation. Parvocellular neurones that originate in the PVN project into multiple areas within CNS. The oxytocin-producing cells are innervated by cholinergic, catecholaminergic, seroronergic as well as peptidergic neurones. The presence of oxytocin in different tissues outside the brain, such as the uterus, ovaries, testis, thymus, adrenal medulla and pancreas has been demonstrated and oxytocin is suggested to exert local effects in these organs. A parallel secretion of oxytocin into the brain regions and into the circulation occurs in response to some stimuli such as suckling, but other stimuli can cause separate activation of oxytocinergic neurones, terminating in the brain or the pituitary.
Cellulose ethers are named after, and based on, cellulose which is a renewable material and the most common chemical compound in organic nature. There is a broad range of cellulose ethers available on the market, both ionic and non-ionic, for example sodium carboxymethylcellulose, hydroxyethylethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose and hydroxypropylmethycellulose.
Cellulose ethers are used as additives in such diverse applications as food, paint, oil recovery, paper, cosmetics, pharmaceuticals, adhesives, printing, agriculture, ceramics, textiles, detergents and building materials. Cellulose ethers improve the product quality in these applications and act as thickeners, water retention agents, suspending aids, protecting colloids, film formers or thermoplastics in such different products as dispersion paints, drilling muds, ice cream, tablet coatings, wallpaper paste and tile adhesive.
Non-ionic cellulose ethers such as methylcellulose, hydroxypropylmethylcellulose (also referred to as hypromellose) and methylhydroxyethylcellulose, are widely used in the pharmaceutical industry due to their ability to thicken, bind and retain water, as well as to emulsify and suspend particles and form films. Further information regarding non-ionic cellulose ethers can be found e.g. in WO92/09307.
The peptide structure of oxytocin makes it vulnerable to degradation, and it is a well-known fact that pharmaceutical compositions comprising oxytocin should be stored in a cool environment (about 4° C.) to avoid substantial degradation and/or aggregation thereby losing its biological function. For example, it is recommended that Syntocinon® (Novartis), a concentrated aqueous solution of oxytocin for injection/infusion, should normally be stored at 2-8° C. The shelf-life at 25° C. for this product is limited to 3 months. Another example is Syntocinon® nasal spray, which also should be stored at 2-8° C. These aqueous formulations comprise buffers, preservatives, acids, salt, co-solvents and other water-soluble additives but no gelling agent.
Previous formulations with oxytocin comprising the ionic gelling agent sodium carboxymethylcellulose (CMC) have been shown to not provide a suitable environment for oxytocin. This is for example illustrated in the experimental section of the present application.
Accordingly, in view of the problems associated with previous pharmaceutical compositions comprising oxytocin, there is a need in the art to overcome or at least mitigate some of the disadvantages in the art by providing pharmaceutical compositions wherein the stability of oxytocin is improved. Such pharmaceutical compositions will provide for more convenient storage, such as in room temperature, and should also retain their biological activity for a longer period of time.